Bioisosteric replacement of the .alpha.-amino carboxylic acid functionality in 2-amino-5-phosphonopentanoic acid yields unique 3,4-diamino-3-cyclobutene-1,2-dione containing NMDA antagonists

Kinney, William A.; Lee, Nancy E.; Garrison, Deanna T.; Podlesny, Edward J.; Simmonds, Joanne T.; Bramlett, Donna R.; Notvest, Ronald R.; Kowal, Dianne; Tasse, Rene

doi:10.1021/jm00103a010

Cited by 52 publications

(27 citation statements)

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“…Its chemical structure which contains an (S)-alanine moiety attached to a five-membered heterocycle was determined by chemical methods, 113,114 synthesis, 115 and X-ray crystallographic studies. 116 In binding studies at native iGluRs, QUIS has been shown to be a nonselective high affinity ligand 117 (Table VII) and furthermore in functional assays QUIS has been shown to be a full agonist. 118 Moreover, QUIS is a potent agonist at the metabotropic receptors (mGluR5: EC 50 ¼ 55 nM).…”

Section: Q U I S Q U a L I C A C I D A N D A N A L O G Smentioning

confidence: 99%

Subtype selective kainic acid receptor agonists: Discovery and approaches to rational design

Bunch

Krogsgaard‐Larsen

2008

Medicinal Research Reviews

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(S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system, activating the plethora of glutamate receptors (GluRs). In broad lines, the GluRs are divided into two major classes: the ionotropic Glu receptors (iGluRs) and the metabotropic Glu receptors (mGluRs). Within the iGluRs, five subtypes (KA1, KA2, iGluR5-7) show high affinity and express full agonist activity upon binding of the naturally occurring amino acid kainic acid (KA). Thus these receptors have been named the KA receptors. This review describes all-to our knowledge-published KA receptor agonists. In total, over 100 compounds are described by means of chemical structure and available pharmacological data. With this perspective review, it is our intention to ignite and stimulate inspiration for future design and synthesis of novel subtype selective KA receptor agonists.

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Section: Q U I S Q U a L I C A C I D A N D A N A L O G Smentioning

confidence: 99%

Subtype selective kainic acid receptor agonists: Discovery and approaches to rational design

Bunch

Krogsgaard‐Larsen

2008

Medicinal Research Reviews

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“…For example, squaric acid and related derivatives have been successfully employed as carboxylic acid surrogates in drug design. 3-6 In similar fashion, cyclopentane-1,3-diones (Figure 1A) are effective substitutes for the carboxylic acid moiety of known thromboxane A 2 (TP) receptor antagonists ( e.g. , 1 , 7 Figure 1C), leading to potent derivatives.…”

mentioning

confidence: 89%

Evaluation of the cyclopentane-1,2-dione as a potential bio-isostere of the carboxylic acid functional group

Ballatore

Gay

Huang

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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Cycloalkylpolyones hold promise in drug design as carboxylic acid bio-isosteres. To investigate cyclopentane-1,2-diones as potential surrogates of the carboxylic acid functional group, the acidity, tautomerism, and geometry of hydrogen bonding of representative compounds were evaluated. Prototypic derivatives of the known thromboxane A2 prostanoid (TP) receptor antagonist, 3-(3-(2-((4-chlorophenyl)sulfonamido)-ethyl)phenyl)propanoic acid, in which the carboxylic acid moiety is replaced by the cyclopentane-1,2-dione unit, were synthesized and evaluated as TP receptor antagonists. Cyclopentane-1,2-dione derivative 9 was found to be a potent TP receptor antagonist with an IC50 value comparable to that of the parent carboxylic acid. These results indicate that the cyclopentane-1,2-dione may be a potentially useful carboxylic acid bio-isostere.

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“…All NMDA receptors possess several binding sites of pharmacological interest including those for glutamate, glycine, polyamines and open channel blockers [129]. A novel squaryl molecular metaphor of the amino acid, 3,4-diamino-3-cyclobutene-1,2-dione, has been incorporated into a series of NMDA antagonists [130]. These achiral compounds have demonstrated an affinity for the NMDA receptor, for example perzinfotel (EAA-090).…”

Section: Kitsonmentioning

confidence: 99%

“…An alternative to the synthesis of substituted cyclobutenediones, is a free radical approach developed by the research group of Kinney [130]. This strategy is used in the presence of the diethoxyphosphinyl group required for the synthesis of potential NMDA antagonists, as well as other functionalities [132].…”

Section: Figure 35 Synthesis Of Phosphonic Acid Squaramidementioning

confidence: 99%

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

Kitson¹

2017

J Diagn Imaging Ther

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Molecular Metaphors is the application of squaryl building blocks towards creative functional group chemistry to produce lead compounds and imaging agents. This strategy is applied to rational drug design and to various imaging agents that would normally contain conventional functional group chemistry. These, include carboxylic acids, α-amino acids, peptide bonds and phosphonates. Moreover, the squaryl metaphor is a precursor to complex organic molecules involving functional group interchange (FGI) and rearrangements. This article discusses the application of these metaphors in the area of neurochemistry, especially NMDA receptors. An important area of drug design is the inhibition of angiotensin II enzyme by the use of losartan. This commercial drug contains a tetrazole moiety that can be modified using the squaryl group to give a semisquarate derivative. These concepts can extend to the semisquarate of ibuprofen. Moreover, a discussion on peptidomimetics regarding the substitution of the peptide bond for squaramide allows for a change in the biological properties due to modification at the peptide bond. Furthermore, the topic on how squaryl metaphors can be exploited primarily by the central 1,3-hydroxyamide sequence to the generation of a novel class of HIV protease inhibitors. Also, squaryl metaphors can be used to develop potential inhibitors of glutathione and novel anti-migraine drugs. The discussion continues on the design of anticancer drugs: in particular, a novel class of metalloproteases, including phosphonates for semisquaramides, leading to squaryl nucleosides. This review concludes with the application of squaryl metaphors in the design of positron emission tomography (PET) and magnetic resonance imaging (MRI) agents towards theranostics. describe the ability of individual functional chemical groups to mimic other moieties [2,3]. KeywordsErlenmeyer rationalised these concepts and categorised isosteres into atoms, ions and molecules based on the valence level of electrons [4]. A further understanding by Friedman led to the term bioisosterism to include all atoms and molecules that fit the broadest definition of isosteres [5]. This approach was independent of whether the drug was an agonist or an antagonist towards biological activity.Moreover, Thornber applied the term bioisosterism to include subunits, groups or molecules that possess physicochemical properties of similar biological effects [6]. Finally, in 1991 Burger widened the definition of bioisosteres to include compounds or groups that possess similar molecular shapes and volumes independent of agonists or antagonists [7]. REVIEW ARTICLE Squaryl KitsonThese bioisosteres would require approximately the same distribution of electrons and give a high probability of generating comparable physical properties such as hydrophobicity [8]. Currently, bioisosterism is one of the most useful tools to the medicinal chemist in rational drug design and in particular regarding the carboxylic acid bioisosteres [9]. The carboxylic acid functional ...

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Bioisosteric replacement of the .alpha.-amino carboxylic acid functionality in 2-amino-5-phosphonopentanoic acid yields unique 3,4-diamino-3-cyclobutene-1,2-dione containing NMDA antagonists

Cited by 52 publications

References 1 publication

Subtype selective kainic acid receptor agonists: Discovery and approaches to rational design

Subtype selective kainic acid receptor agonists: Discovery and approaches to rational design

Evaluation of the cyclopentane-1,2-dione as a potential bio-isostere of the carboxylic acid functional group

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

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